The first responders to sites of infections and tissue injury are neutrophils, innate immune cells with a broad repertoire of effector functions including phagocytosis, degranulation, generation of reactive oxygen species (ROS) by the NADPH oxidase NOX2, extracellular chromatin release (NETs) and cytokine secretion. These cells are critical for antimicrobial killing and host defense, direct some aspects of adaptive immunity and participate in healing responses, but neutrophils may also contribute to excessive inflammation and tissue damage in severe, persistent disease. Almost all acute and many chronic respiratory and intestinal infections, and certain chronic inflammatory diseases are characterized by elevated numbers of activated neutrophils. When considering neutrophils in disease outcome, the line between beneficial and harmful seems quite narrow. Flexible adaptation of neutrophils due to phenotypical and functional plasticity may provide an explanation, resulting in various neutrophil subtypes by up- or downregulating genes and granule contents, or in phenotypic conversions by genetic reprogramming via environmental cues. In the disease context these cues will likely be linked to certain settings with comparable microenvironments such as the respiratory and gastrointestinal tract. We discovered similar features of neutrophil plasticity, induced by genetic reprogramming, in humans and mice in respiratory infections and intestinal inflammation. One of the acquired changes was the de novo high level expression of an additional oxidant-generating enzyme. This project will increase patient numbers and broaden the disease context of this observation in humans and mice and will perform a harm-benefit analysis for the expression of this enzyme in neutrophils using preclinical mouse models. These studies are a prerequisite for developing drugs modulating disease-associated neutrophil phenotypes in infection and inflammation.
